Phenylpiperazines

ABSTRACT

The invention relates to a novel group of phenylpiperazines having interesting pharmacological properties such as a high affinity for the dopamine D 2  receptor and/or the serotonin reuptake site, and the ability to treat conditions related to disturbances in the dopaminergic and/or the serotonergic systems such as anxiety disorders, depression, Parkinson&#39;s disease, and schizophrenia. 
     The invention relates to a group of novel phenylpiperazine derivatives of the formula (I): 
                         
wherein:
         X is a group of formula 1, 2, 3, 4, 5, 6, or 7 as defined in the text,   m has the value 2 to 6;   n has the value 0-2;   R 5  and R 6  are independently H or alkyl (1-3C); or R 5 +R 6  represent a group —(CH 2 )— p  wherein p has the value 3-5, and   R 7  is alkyl (1-3C), alkoxy (1-3C), halogen or cyano; or R 6 +R 7  (R 7  at position 7 of the indole group) represent a group —(CH 2 ) q  wherein q has the value 2-4, and salts thereof.

This is a divisional of application Ser. No. 10/069,256, which wasaccepted under 35 U.S.C. § 371 on Sep. 12, 2002, and claims priority ofpriority of International Application PCT/EP00/08190, filed Aug. 22,2000, which claims the priority of European Patent Application99202710.2, filed Aug. 23, 1999, and Netherlands Patent Application1012888, filed Aug. 23, 1999, all of which are incorporated herein byreference.

The invention relates to a group of novel phenylpiperazine derivativesof the formula (I):

wherein:

-   -   X is 1) a group of the formula

wherein

-   -   S₁ is hydrogen or halogen,    -   S₂ and S₃ are independently hydrogen, alkyl (1-6C), phenyl or        benzyl,    -   S₄ represents two hydrogen atoms or an oxo group,    -   S₅ is H or alkyl (1-4C), and    -   Y is CH₂, O or S or 2) a group of the formula

wherein S₁ has the above meaning and Z is CH₂, O or NH, (2-6C), alkenyl(2-4C) or alkynyl (2-4C), or 3) a group of the formula

wherein S₁ has the above meaning and Z is C, O or N, or 4) a group ofthe formula

wherein S₁ has the above meaning, or 5) a group of the formula

wherein S₁ has the above meaning and A is O or NH, linked to thepiperazine ring with position 5 or 8, or 6) a group of the formula

wherein S₁ has the above meaning and S₆ and S₇ represent hydrogen atomsor an oxo group, or 7) a group of the formula

wherein one of the dotted lines can represent a double bond, S₁ has theabove meaning, and P, T, and Q are independently nitrogen or NH

or P and T are independently nitrogen or NH and Q is CH or CH₂

or P and Q are independently nitrogen or NH and is CH, CH₂, C-CH₃ orCH-CH₃

or P is nitrogen or NH, and T and Q are independently CH or CH₂ or P isnitrogen or NH, T is CH or CH₂ and Q is sulphur

-   -   m has the value 2 to 6;    -   n has the value 0-2;    -   R₅ and R₆ are independently H or alkyl (1-3C); or R₅+R₆        represent a group —(CH₂)-_(p) wherein p has the value 3-5, and    -   R₇ is alkyl (1-3C), alkoxy (1-3C), halogen or cyano; or R₆+R₇        (R₇ at position 7 of the indole group) represent a group        —(CH₂)_(q) wherein q has the value 2-4, and salts thereof, which        show high affinity for the dopamine D₂-receptor and are good        serotonin reuptake inhibitors (SRI's).

Preferred compounds of the invention are compounds having formula (I)wherein X represents a group of the formula (1), (2) or (3), wherein thesymbols have the meanings given above and the salts thereof. Especiallypreferred are compounds having formula (I) wherein X is the group withthe formula (1) wherein S₁=H, S₂=CH₃, S₃=H, S₄=oxo, S₅=H and Y isoxygen, m is 3, R₅=R₆=hydrogen, n is 0 or 1 and R₇ is 5-fluoro, and thesalts thereof.

It has been found that the compounds according to the invention showhigh affinity for both the dopamine D₂ receptor and the serotoninreuptake site. This combination is useful for the treatment ofschizophrenia and other psychotic disorders which enables a morecomplete treatment of all disease symptoms (e.g. positive symptoms andnegative symptoms).

However, some of the compounds having formula (I) show (partial) agonistactivity at dopamine receptors making them particularly suitable for thetreatment of Parkinson's disease.

The compounds show activity as antagonists at dopamine D₂ receptors asthey potentially antagonize apomorphine-induced climbing behaviour inmice. The compounds also show activity as inhibitors of serotoninreuptake, as they potentiate 5-HTP induced behaviour in mice.

The compounds are active in therapeutic models sensitive to clinicallyrelevant antipsychotics (e.g. the conditioned avoidance response; Vander Heyden & Bradford, Behav. Brain Res., 1988, 31:61-67) andantidepressants or anxiolytics (e.g. suppression of stress-inducedvocalization; van der Poel et al., Psychopharmacology, 1989, 97:147-148).

In contrast to clinically relevant dopamine D₂ receptor antagonists thedescribed compounds have a low propensity to induce catalepsy in rodentsand as such are likely to induce less extrapyramidal side effects thanexisting antipsychotic agents.

The inhibitory activity of serotonin reuptake inherent in thesecompounds may be responsible for the therapeutic effects observed inbehavioural models sensitive to either antidepressants or anxiolytics.

The compounds can be used for the treatment of affections or diseases ofthe central nervous system caused by disturbances in either thedopaminergic or serotonergic systems, for example: aggression, anxietydisorders, autism, vertigo, depression, disturbances of cognition ormemory, Parkinson's disease, and in particular schizophrenia and otherpsychotic disorders.

Pharmacologically acceptable acids with which the compounds of theinvention can form suitable acid addition salts are for examplehydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, andorganic acids such as citric acid, fumaric acid, maleic acid, tartaricacid, acetic acid, benzoic acid, p-toluene sulphonic acid,methanesulphonic acid and naphthalene sulphonic acid.

When the compounds comprise a centre of chirality both the racemicmixture and the individual enantiomers belong to the invention.

The compounds and their acid addition salts can be brought into formssuitable for administration by means of suitable processes usingauxiliary substances such as liquid and solid carrier materials.

The compounds having formula (I) can be prepared by reaction of acompound of the formula

under basic conditions with a compound of the formula

in which formulae the symbols have the meanings given above, and L is aso-called leaving group such as a halogen atom or a mesylate group.

The piperazine compounds having formula (II) can be obtained asdescribed in EP 0138280, EP 0189612 and/or EP 0900792, or in ananalogous manner.

The preparation of the piperazines having formula (II) can be carriedout as indicated in schemes (i)-(iv) below. Some of the routes result inoptically pure piperazine derivatives.

The starting compounds having formula (III) can be prepared according tomethods known for analogues compounds, as described for example inOrganic Process Res. and Dev. 1997 (1), 300-310.

The invention will now be illustrated by means of the followingExamples:

EXAMPLE 1 Preparation of Compound a,i (See Scheme i)

Step 1 (scheme i): To a solution of chloronitrocatechol (6.45 g, 34mmol) in dry DMSO (50 ml) was added powdered NaOH (2.72 g, 68 mmol).After stirring for 30 minutes a solution was added of R-glycerolketalmesylate (8.0 g, 38 mmol) in DMSO (20 ml) and this mixture was heated at80° C. during 24 hours. After cooling to room temperature the reactionmixture was poured into water (200 ml), acidified with 1 N HCl andextracted with methyl t-butylether. The organic fraction was washed withwater and dried on MgSO₄. After removal of the drying agent and thesolvent in vacuo, the resulting oil was subjected to flash chromatografy(SiO₂, eluent PE/aceton=3/1). Yield 9.29 g (90%) of the S-ketal.

Step 2 (scheme i): To a solution of the S-ketal (31 g, 102 mmol) inacetic acid (120 ml) was added 35% HBr in acetic acid (80 ml) and thismixture was rotated for 2 hours on a rotavapor in a waterbath of 50° C.The reaction mixture was diluted with ethanol (96%, 250 ml), cooled in asalt/ice mixture and then NaOH (50% in water, 250 ml) was added slowly,keeping the temperature below 15° C. After adding ethanol (250 ml) andwater (250 ml) the reaction mixture was stirred at room temperature for16 hours. Then concentrated HCI (about 300 ml) and water were added andthe mixture extracted with ethyl acetate. After washing the organicfraction with 5% NaHCO₃ (4×500 ml), the solvent was removed in vacuo andthe resulting oil was subjected to flash chromatografy (SiO₂, eluentPE/aceton=3/1). Yield 20.5 g (81 %) of the R-benzodioxane as a yellowoil.

Step 3 (scheme i): To a solution of R-benzodioxane (20 g, 81 mmol) inDMF (200 ml) was added KOH (4.56 g, 81 mmol). After cooling the redsolution in ice/aceton dimethyl sulfate (23 ml) was added and thereaction mixture was stirred for 1.5 hours at room temperature. Thenmore KOH (4.56 g, cooling) was added and the mixture was stirred at roomtemperature for 16 hours. After adding water (700 ml), the product wasextracted with ethyl acetate. The ethyl acetate was removed in vacuo andthe resulting oil was subjected to flash chromatografy (SiO₂, eluentPE/aceton=4/1) yielding R-methoxymethylbenzodioxane (12.3 g, 58%) as ayellow oil. [α]_(D) ²⁵=−97° (methanol).

Step 4 (scheme i): To a solution of R-methoxymethylbenzodioxane (5 g, 19mmol) in ethanol (100 ml) and ethyl acetate (50 ml) was added acatalytic amount of 10% Pd/C and the solution was shaken underatmospheric H₂ pressure at room temperature. After the calculated amountof H₂ was taken up by the reaction mixture, the catalyst was removed byfiltration and the filtrate was concentrated in vacuo. Yield 3.7 g(100%) of the corresponding anilino-compound.

Step 5 (scheme i): The anilino-compound (4 g, 2 mmol) and BCEA, i.e.HN(CH₂CH₂CI)₂.HCl (3.7 g, 2 mmol) were dissolved in chlorobenzene (100ml). The mixture was heated to 150° C. for 16 hours, concentrated invacuo and purified by flash chromatografy (SiO₂,dichloromethane/methanol/ammonium hydroxide=92/7.5/0.5). Yield 3.67 g(68%) of the piperazine a,i.

EXAMPLE 2 Preparation of Compound No. 126

The route is described above, i.e. reaction of compound (II) withcompound (III). The mesylates of formula (III) were prepared from thecorresponding alcohols by standard procedures, e.g. with MsCI/Et₃N.

A mixture of the piperazine a,i (3,6 g, 13,6 mmol), the 5-fluoroindole-mesylate (4,1 g, 15,1 mmol), triethylamine (2 ml) and a catalyticamount of KI in CH₃CN (100 ml) was heated under reflux during 18 hoursafter which the reaction mixture was concentrated in vacuo and purifiedby chromatografy (SiO₂, dichloromethane/methanol/ammoniumhydroxide=92/7.5/0.5). Yield 3,77 of the free base (oil). The free basewas dissolved in ethanol and 1 equivalent of fumaric acid in ethanol wasadded. After removal of the solvent compound no. 126 was obtained (4,3g, 57%). [α]_(D) ²⁵=−2 ° (methanol)

EXAMPLE 3 Preparation of Compound b,ii (See Scheme ii)

Step 1 (scheme ii): A solution of the aminophenol (37.3 g, 198 mmol),S-lactic acid methyl ester (20 ml) and triphenylphosphine (58 g, 220mmol) in THF (2000 ml) was cooled in ice/salt (temperature <10° C.).Then a solution of azodicarboxic acid ester (DIAD, 43 ml, 218 mmol) inTHF (400 ml) was added slowly. After stirring at room temperature for 18hours the reaction mixture was concentrated in vacuo and ethanol (500ml) and 36% HCl (125 ml) were added to the residue. The mixture washeated to 100° C. (development of gas). After cooling the compound wasisolated by filtration and washed with 96% ethanol (about 100 ml). Yield42 g (87%).

Step 2 (scheme ii): This step is similar to step 4 described in schemei.

Step 3 (scheme ii): This step is similar to step 5 described in schemei, resulting in the formation of the piperazine b,ii.

EXAMPLE 4 Preparation of Compound No. 89

The route is described above, i.e. reaction of compound (II) withcompound (III). The reaction is carried out as described in example 2,starting with the piperazine b,ii. Yield 58% of compound no. 89, [α]_(D)²⁵==24° (methanol).

EXAMPLE 5 Preparation of Compound c,iii (See Scheme iii)

Step 1 (scheme iii): A solution of the benzomorpholinone (10 g, 41 mmol; see scheme ii, step 1) and powdered KOH (2.3 g, 41 mmol) in DMF (100ml) was cooled in ice (temperature <10° C.). After adding 1 equivalentof Mel (2.55 ml, 41 mmol) the reaction mixture was stirred at roomtemperature for about 1.5 hours and then poured into water. Theprecipitate was filtered off, washed with water and dried. Yield 10 g(95%) of the NCH₃₋-compound, mp. 191-192; [α]_(D) ²⁵=+7.50° (in THF)

Step 2 (scheme iii): This step is similar to step 4 described in schemei.

Step 3 (scheme iii): This step is similar to step 5 described in schemei, resulting in the formation of the piperazine c,iii.

EXAMPLE 6 Preparation of Compound No. 121

The route is described above, i.e. reaction of compound (II) withcompound (III). The reaction is performed as described in example 2,starting with the piperazine c,iii. Yield 44% of compound no. 121,[α]_(D) ²⁵=−28° (methanol).

EXAMPLE 7 Preparation of Compound d,iv (See Scheme iv)

Step 1 (scheme iv): Pyridine (81 ml, 1 mol) was added to a solution of2-hydroxy-5-chloroaniline (143.5 g, 1 mol) in dry CH₂Cl₂. The mixturewas cooled in ice (temperature <10° C.) and then a solution of2-bromo-2-methyl-propionylbromide (163 ml, 1 mol) in CH₂Cl₂ (100 ml) wasadded slowly. The mixture was stirred at room temperature for 18 hoursand was poured into CH₂Cl₂ (5000 ml) and water (2000 ml). The organiclayer was washed with water, dried and concentrated in vacuo till about1 litre. The precipitate was filtered off, washed with CH₂Cl₂ and dried.Yield 231 g (79%) of the bromocompound, mp. 172° C.

Step 2 (scheme iv): To a suspension of the bromocompound (60 g, 205mmol) in water (95 ml) was added slowly under ice cooling concentratedsulfuric acid (7 ml) followed by 70% HNO₃ (16 ml) and stirring wascontinued for 2 hours at room temperature. After cooling in ice waterthe precipitate was filtered off, washed with water and purified bychromatografy (SiO₂, methyl t-butylether). Yield 49 g (71%) of thenitrocompound.

Step 3 (scheme iv): To a solution of the nitrocompound (49 g, 145 mmol)in DMF (500ml) was added K₂CO₃. This mixture was heated for one hour at150° C., then cooled and poured into a mixture water/ethyl acetate. Theorganic fraction was washed with sodium bicarbonate (5% in water), HCl(2N) and water respectively. The solvent was removed in vacuo and theresidue was purified by flash chromatografy (SiO₂, methylt-butylether/PE =1/1). Yield 23 g (62%).

Step 4 (scheme iv): This step is similar to step 4 described in schemei.

Step 5 (scheme iv): This step is similar to step 5 described in schemei, leading to the formation of the piperazine d,iv.

EXAMPLE 8 Preparation of Compound No. 115

The route is described above, i.e. reaction of compound (II) withcompound (III). The reaction is performed as described in example 2,starting with the piperazine d,iv. Yield 20% of compound no. 115.

The compounds listed in the following tables have been preparedaccording to the method of the above examples.

Comp. no X m Y R₅ R₆ (R₇)n R Z A S₆ + S₇ P T Q Remarks 26 form 3 3 — H H7-F — O — — — — — S₁ = H 27 1 3 CH₂ H H 7-F — — — — — — — S₁–S₅ = H 28 33 — H H 7-Cl — O — — — — — S₁ = H 29 3 3 — H H 7-CH₃ — O — — — — — S₁ =H 30 2 3 — H H H 2-CH₂OCH₃ — — — — — — S₁ = H 31 7 3 — H H H — — — — NCH₂ CH₂ S₁ = H 32 1 3 CH₂ H H 6-Cl — — — — — — — S₁–S₅ = H 33 3 3 — H H6-Cl — O — — — — — S₁ = H 34 3 3 — H H 5-CN — O — — — — — S₁ = H 35 1 3CH₂ H H 5-CN — — — — — — — S₁–S₅ = H 36 1 3 CH₂ H H 4-Cl — — — — — — —S₁–S₅ = H 37 3 3 — H H 4-Cl — O — — — — — S₁ = H 38 1 6 CH₂ H H H — — —— — — — S₁–S₅ = H 39 1 5 CH₂ H H H — — — — — — — S₁–S₅ = H 40 1 3 CH₂ HH H — — — — — — — S₁–S₄ = H S₅ = CH₃ 41 1 3 S H H H — — — — — — — S₄ =oxo, S₁–S₃ = S₅ = H 42 6 3 — H H H — — — oxo — — — S₁ = H 43 1 3 S H H H— — — — — — — S₁–S₅ = H 44 6 3 — H H H — — — H₂ — — — S₁ = H 45 1 4 CH₂H H H — — — — — — — S₁–S₅ = H 46 1 3 CH₂ H H 6-F — — — — — — S₁–S₅ = H47 3 3 — H H 6-F — O — — — — — S₁ = H 48 7 3 — H H H — — — — N CH NH S₁= H 49 1 3 O H H H — — — — — — — S₄ = oxo, S₂ = CH₃, S₁ = S₃ = S₅ = H 501 3 CH₂ H H H — — — — — — — S₄ = oxo, S₁–S₃ = S₅ = H 51 form 3 3 — HC₂H₅ 5-CN — O — — — — — S₁ = H 52 3 3 — H H H — NH — — — — — S₁ = H 53 73 — H H H — — — — N C(CH₃) NH S₁ = H 54 7 3 — H H H — — — — NH N CH S₁ =H 55 7 3 — H H H — — — — N N NH S₁ = H 56 1 3 CH₂ H H 4-F — — — — — — —S₁–S₅ = H 57 3 3 — H H 4-F — O — — — — — S₁ = H 58 1 3 CH₂ H H 7-Br — —— — — — — S₁–S₅ = H 59 3 3 — H H 7-Br — O — — — — — S₁ = H 60 1 3 O H HH — — — — — — — S₄ = oxo, S₁ = 7-Cl, S₂ = S₃ = S₅ = H 61 2 3 — H H 5-F2-CH₂OCH₃ — — — — — — S₁ = H 62 1 3 CH₂ H H 5,7-F₂ — — — — — — — S₁–S₅ =H 63 3 3 — H H 5,7-F₂ — O — — — — — S₁ = H 64 2 3 — H H 7-F 2-CH₂OCH₃ —— — — — — S₁ = H 65 5 3 — H H H — — NH — — — — S₁ = H; position 5 66 5 3— H H 5-F — — NH — — — — S₁ = H; position 5 67 5 3 — H H 7-F — — NH — —— — S₁ = H; position 5 68 2 3 — H H H 3-CH₂OCH₃ — — — — — — S₁ = H 69 23 — H H H 2-CH₂OCH₃ — — — — — — S₁ = H 70 2 3 — H H 5-F 2-CH₂OCH₃ — — —— — — S₁ = H 71 2 3 — H H 5-F 3-CH₂OCH₃ — — — — — — S₁ = H 72 2 3 — H H7-F 3-CH₂OCH₃ — — — — — — S₁ = H 73 2 3 — H H 7-F 2-CH₂OCH₃ — — — — — —S₁ = H 74 1 3 S H H 5-F — — — — — — — S₄ = oxo, S₁–S₃ = S₅ = H 75 2 3 —H H H 3-CH₂OC₃H₇ — — — — — — S₁ = H 76 form. 2 3 — H H 5-F 3-CH₂OC₃H₇ —— — — — — S₁ = H 77 2 3 — H H H 3-CH₂OCH₂C═CH — — — — — — S₁ = H 78 2 3— H H 5-F 3-CH₂OCH₂C═CH — — — — — — S₁ = H 79 2 3 — H H 7-F3-CH₂OCH₂C═CH — — — — — — S₁ = H 80 2 3 — H H H 3-CH₂OCH₂CH₂OCH₃ — — — —— — S₁ = H 81 2 3 — H H 5-F 3-CH₂OCH₂CH₂OCH₃ — — — — — — S₁ = H 82 2 3 —H H 7-F 3-CH₂OCH₂CH₂OCH₃ — — — — — — S₁ = H 83 1 3 S H H 5-F — — — — — —— S₁–S₅ = H 84 1 3 S H H H — — — — — — — S₂ = CH₃, S₁ = S₃–S₅ = H 85 1 3S H H H — — — — — — — S₄ = oxo, S₂ = CH₃, S₁ = S₃ = S₅ = H 86 7 3 — H HH — — — — N CH S S₁ = H 87 1 3 O H H H — — — — — — — S₄ = oxo, S₂ = CH₃,S₁ = S₃ = S₅ = H 88 1 3 O H H H — — — — — — — S₄ = oxo, S₂ = CH₃, S₁ =S₃ = S₅ = H 89 1 3 O H H 5-F — — — — — — — S₄ = oxo, S₂ = CH₃, S₁ = S₃ =S₅ = H 90 1 3 O H H 5-F — — — — — — — S₄ = oxo, S₂ = CH₃, S₁ = S₃ = S₅ =H 91 1 3 O H H 7-F — — — — — — — S₄ = oxo, S₂ = CH₃, S₁ = S₃ = S₅ = H 921 3 O H H 7-F — — — — — — — S₄ = oxo, S₂ = CH₃, S₁ = S₃ = S₅ = H 93 1 3O H H H — — — — — — — S₄ = oxo, S₂ = phenyl, S₁ = S₃ = S₅ = H 94 1 3 O HH 5-F — — — — — — — S₄ = oxo, S₂ = phenyl, S₁ = S₃ = S₅ = H 95 1 3 O H H7-F — — — — — — — S₄ = oxo, S₂ = phenyl, S₁ = S₃ = S₅ = H 96 2 3 — H H H3-CH₂OCH₂CH═CH₂ — — — — — — S₁ = H 97 2 3 — H H 5-F 3-CH₂OCH₂CH═CH₂ — —— — — — S₁ = H 98 2 3 — H H 7-F 3-CH₂OCH₂CH═CH₂ — — — — — — S₁ = H 99 23 — H H H 2-CH₂OCH₂C═CH — — — — — — S₁ = H 100 2 3 — H H 5-F2-CH₂OCH₂C═CH — — — — — — S₁ = H 101 form. 2 3 — H H 7-F 2-CH₂OCH₂C═CH —— — — — — S₁ = H 102 1 3 O H H H — — — — — — — S₄ = oxo, S₂ = C₃H₇, S₁ =S₃ = S₅ = H 103 1 3 O H H 5-F — — — — — — — S₄ = oxo, S₂ = C₃H₇, S₁ = S₃= S₅ = H 104 1 3 O H H 7-F — — — — — — — S₄ = oxo, S₂ = C₃H₇, S₁ = S₃ =S₅ = H 105 1 3 O H H H — — — — — — — S₄ = oxo, S₂ = S₅ = CH₃, S₁ = S₃ =H 106 1 3 O H H 5-F — — — — — — — S₄ = oxo, S₂ = S₅ = CH₃, S₁ = S₃ = H107 1 3 O H H 7-F — — — — — — — S₄ = oxo, S₂ = S₅ = CH₃, S₁ = S₃ = H 1081 3 O H H H — — — — — — — S₄ = oxo, S₂ = benzyl, S₁ = S₃ = S₅ = H 109 13 O H H 5-F — — — — — — — S₄ = oxo, S₂ = benzyl, S₁ = S₃ = S₅ = H 110 13 O H H 7-F — — — — — — — S₄ = oxo, S₂ = benzyl, S₁ = S₃ = S₅ = H 111 23 — H H H 3-CH₂OCH₂C═CCH₃ — — — — — — S₁ = H 112 2 3 — H H H2-CH₂OCH₂C═CCH₃ — — — — — — S₁ = H 113 2 3 — H H 5-F 2-CH₂OCH₂C═CCH₃ — —— — — — S₁ = H 114 1 3 O H H H — — — — — — — S₄ = oxo, S₂ = S₃ = CH₃, S₁= S₅ = H 115 1 3 O H H 5-F — — — — — — — S₄ = oxo, S₂ = S₃ = CH₃, S₁ =S₅ = H 116 2 3 — H H H 3-CH₂OCH₃ — — — — — — S₁ = H 117 2 3 — H H 5-F3-CH₂OCH₃ — — — — — — S₁ = H 118 2 3 — H H 5-F 3-CH₂OCH₃ — — — — — — S₁= H 119 2 3 — H H H 3-CH₂OCH₃ — — — — — — S₁ = H 120 1 3 O H H H — — — —— — — S₄ = oxo, S₂ = S₅ = CH₃, S₁ = S₃ = H 121 1 3 O H H 5-F — — — — — —— S₄ = oxo, S₂ = S₅ = CH₃, S₁ = S₃ = H 122 1 3 O H H 5-F — — — — — — —S₄ = oxo, S₂ = S₅ = CH₃, S₁ = S₃ = H 123 1 3 O H H H — — — — — — — S₄ =oxo, S₂ = S₅ = CH₃, S₁ = S₃ = H 124 1 3 O H H 5-F — — — — — — — S₄ =oxo, S₁ = 7-Cl, S₂ = S₃ = S₅ = CH₃ 125 1 3 O H H 5-F — — — — — — — S₄ =oxo, S₁ = H, S₂ = S₃ = S₅ = CH₃ 126 2 3 — H H 5-F 3-CH₂OCH₃ — — — — — —S₁ = H *R₇ is linked to position 7 of the indole group

Comp. [α]_(D) ²⁵ (in no Salt or free base MP(° C.) methanol) 1 fumarate192-4 — 2 2-HCl 239-41 — 3 free base 203-4 — 4 ″ 170-1 — 5 3.fumarate 98— 6 free base 175-6 — 7 4/3. fumarate 140-3 — 8 free base 189-90 — 9fumarate 200-1 — 10 3/2. fumarate 190-1 — 11 ½. fumarate 210-2 (dec.) —12 free base 165-7 — 13 free base 70-1 — 14 fumarate 208 — 15 free baseamorph — 16 2. fumarate amorph — 17 free base amorph — 18 fumarate >225(dec.) — 19 fumarate >170 (dec.) — 20 free base amorph — 21 ½.fumarate >245 (dec) — 22 ½. fumarate >165 glass) — 23 free base 176-7 —24 free base amorph — 25 ½. fumarate amorph — 26 ¾. fumarate amorph — 27½. fumarate >240 (dec) — 28 ⅘. fumarate amorph — 29 ″ amorph — 30 3/2.fumarate glass — 31 5/4. fumarate 188-190 — 32 ½. fumarate >230 (dec) —33 fumarate amorph — 34 fumarate 150-2 — 35 ½. fumarate 247-8 (dec) — 36½. fumarate >240 (dec) — 37 fumarate amorph — 38 HCl amorph — 39 HClamorph — 40 HCl 220-4 — 41 HCl >250 (dec) — 42 ½. fumarate 214-7(dec) —43 ½. fumarate 240-3 — 44 ½. fumarate 220-2(dec) — 45 HCl amorph — 46fumarate 223-5 — 47 ⅔. fumarate 200-2 — 48 free base glass — 49 freebase 196-7 — 50 free base 181-2 — 51 ½. fumarate 138.5-41 — 52 free base190-5(dec) — 53 free base glass — 54 free base glass — 55 free baseglass — 56 ½. fumarate 185-6 — 57 fumarate 210-1(dec) — 58 2. fumarateamorph — 59 free base amorph — 60 ½. fumarate >250 — 61 fumarate glass —62 ½. fumarate 245-7 — 63 3/2. fumarate 175-8 — 64 fumarate glass — 65free base 220-4(dec) — 66 free base 234-6(dec) — 67 free base >280 — 68HCl glass — 69 fumarate glass +28 (free base), R-conf. 70 fumarate glass+28 (free base), R-conf. 71 fumarate glass — 72 fumarate glass — 73fumarate glass +25 (free base), R-conf. 74 free base 212.5-14.5 — 75fumarate glass — 76 fumarate glass — 77 fumarate glass — 78 fumarateglass — 79 fumarate glass — 80 fumarate glass — 81 fumarate glass — 82fumarate glass — 83 fumarate amorph — 84 free base amorph — 85 free baseamorph — 86 ½. fumarate 218-20 — 87 free base glass −26 R-conf. 88 freebase glass +27 S-conf. 89 free base glass −24 R-conf. 90 free base glass+24 S-conf. 91 free base 184-5 −25 R-conf. 92 free base 181-3 +25S-conf. 93 free base glass — 94 free base glass — 95 free base glass —96 free base 70-3 — 97 free base 73-5 — 98 fumarate glass — 99 fumarateglass +39 (free base), R-conf. 100 fumarate glass +36 (free base),R-conf. 101 fumarate glass +37 (free base), R-conf. 102 free base 158-60— 103 free base 181-2 — 104 free base 174-6 — 105 free base glass — 106free base glass — 107 free base glass — 108 free base glass — 109 freebase 207-10(dec) — 110 free base 197-9(dec) — 111 fumarate glass — 112fumarate glass +31 (free base), R-conf 113 fumarate glass +31 (freebase), R-conf 114 free base 191-4 — 115 free base 190-2 — 116 free baseamorph 0 S-conf. 117 fumarate amorph S-conf. 118 free base amorphR-conf. 119 free base amorph 0 R-conf. 120 free base amorph −31 R-conf.121 free base amorph −28 R-conf. 122 free base amorph +28 S-conf. 123free base amorph +32 S-conf. 124 free base amorph — 125 free base amorph— 126 fumarate amorph −2 R-conf.

1. A compound of the formula (I):

wherein: X is a group of the formula m has the value 2 to 6; n has thevalue 0-2; R₅ and R₆ are independently H or alkyl (1-3C); or R₅+R₆represent a group —(CH₂)-_(p) wherein p has the value 3-5, and R₇ isalkyl (1-3C), alkoxy (1-3C), halogen or cyano; or R₆+R₇ (R₇ at position7 of the indole group) represent a group —(CH₂)_(q) wherein q has thevalue 2-4, or a salt of any of the foregoing.
 2. A method for preparinga compound, an enantiomer thereof, or a salt of any of the foregoing asclaimed in claim 1, comprising reacting a compound having formula (II)

wherein S1 is chosen rom hydrogen and halogen and Z is chosen fromCH_(2, O) and NH, under basic conditions with a compound having formula(Ill)

in which formulae the symbols having the meanings given in claim 1, andL is a leaving group, to yield the compound, or the salt of any of theforegoing as claimed in claim
 1. 3. A pharmaceutical compositioncomprising at least one compound as claimed in claim 1, or a salt of anyof the foregoing and at least one auxiliary substance.
 4. A method ofpreparing a composition as claimed in claim 3, comprising mixing the atleast one compound, or a salt of any of the foregoing with the at leastone auxiliary substance.
 5. A method of treating at least one centralnervous system disorder in a human or animal patient in need of suchtreating, comprising administering at least one compound as claimed inclaim 1, a salt of any of the foregoing, or a combination of theforegoing to the patient in an amount effective for the treating,wherein the at least one central nervous system disorder is chosen fromanxiety disorders, depression, Parkinson′s disease, and schizophrenia.6. The method of claim 5, in which the at least one central nervoussystem disorder is chosen from schizophrenia.